Diuretic compounds and method of promoting diuresis



United States Patent 3,345,263 7 DIURETIC COMPOUNDS AND METHOD OF PROMOTING DIURESIS Anangur V. Subbaratnam, Chicago, 11]., assignor to Wilson a & Co., Iuc., a corporation of Delaware No Drawing. Filed June 15, 1964, Ser. No. 375,355 9 Claims. (Cl. 16765) ABSTRACT OF THE DISCLOSURE This application relates to novel substituted cinnamic acids and pharmacologically acceptable salts thereof which have a halogen at either the 3 position or 4 position or both, on the benzene ring of the acid. These compounds are diuretic agents.

This invention relates to therapeutic agents. More par ticularly, it relates to the compounds which are highly effective as diuretic agents. Still more particularly, the invention relates to a method of inducing or promoting a high rate of urine flow and electrolyte excretion by administration of pharmacologically active dosages of compounds falling in the category of derivatives of cinnamic acid.

In accordance with the present invention a compound or mixture of compounds selected from the class identifiable generally as halogen substituted cinnamic acids and the water-soluble salts formed by the use of pharmacologically acceptable cations, either alone or in com bination with known diuretics or saluretics or pharmaceutically acceptable carrier is administered to induce increased flow of urine and electrolyte excretion with minimal side effects.

Diuretics are important pharmaceuticals and are-used extensively to augment the output of waste fluids and thereby to produce a significant loss of body Weight, to reduce or eliminate edema or other symptoms usually associated with hypertension and the retention of an excessive amount of sodium ions in the body.

The classical diuretics, Mercurials and Xanthenes have become restricted in use because it is now recognized that they are toxic upon acute or chronic administration. These compounds also cause side efifects such as local inflammation, ecchymosis and plasma electrolyte imbalance. Y

- In recent years, newer diuretics such as the substituted quinazolinones, acetazolamide, chlorthiazide, hydrochlorthiazide, have come into use. While such compounds do not have the side eflFects of the earlier diuretics, they do have disadvantages such as causing hypokalemia, hyperuricemia and metabolic acidosis. These disturbances of electrolyte balance are undesirable because they can result in listlessness, weakness, apathy and cardiac malfunction. 7

Another disadvantage of many of the diuretics currently in use is that they do not produce an increase in glomerular filtration rate or increase renal plasma flow as indicated by creatinine and para-amino-hippuric acid clearance rates, standard tests as described in Principles of Renal Physiology, Homer W. Smith (1956),. New York; Oxford University Press,- whereas both actions are desirable for fast, efiFective reduction in the quantities of water and salt Which may be retained in the body tissues.

3,345,263 Patented Oct. 3, 1967 wherein R represents a member selected from the group consisting of hydrogen, sodium, potassium, or other phar- 1 macologically acceptable cation; R represents a member selected from the group consisting of hydrogen, an alkyl radical having up to 3 carbon atoms, i.e., methyl, ethyl and n-propyl, isopropyl radicals, halogen radicals, phenyl radical, substituted phenyl radical and carboxyl 2 radical; R represents a member selected from the group consisting of hydrogen and halogen radical; R represents a member selected from the group consisting of hydrogen and halogen radical, at least one of the substituents R and R always being a halogen radical, are elfective non- 2 toxic diuretics capable of inducing an increase in both glomerular filtration rate and renal plasma flow and may be administered alone or in combination with a pharmaceutically acceptable carrier, the proportions of which are determined by the solubility and chemical nature of the compound, the chosen route of administration, etc., to

induce or promote diuresis in mammals without producing undesirable side eifects and without loss of eifectiveness upon prolonged administration.

Representative compounds useful for the purposes of this invention and falling within the generic structural formula indicated above are the free acids and watersoluble salts of nuclear substituted cinnamic acid, such as 3,4-dichloro cinnamic acid, 3-fiuoro potassium cinnamate, 4-chloro potassium cinnamate, 4-bromo cinnamic acid, 3-bromo cinnamic acid, 3,4-dichloro-alpha-methyl I cinnamic acid, 3,4-dichloro-alpha (-p-nitro phenyl) cinnamic acid, (cis and trans) g p I The preferredcompounds for use as diuretics are the 3,4 'dihalogen substituted cinnamic acids, of which, 3,4

dichloro cinnamic acid is a specific example. i

In administering the compounds capable of inducing increased urine flow, such compounds may be administered orally in the form of tablets or capsules, which forms may have water soluble coatings such as the synthetic gum carboxymethylcellulose, gelatin, and the like, and may containstarch, milk sugar, etc., as diluents. They may be administered sublingually in the form of soluble troches, etc. They may also be administered parenterally, that is intrainuscularly, intravenously, or subcutaneously. For parenteral administration, the compounds may be used in the formof a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic, or in solution, suspension or emulsion in liquid carriers such as vegetable oil.

A physicianis best qualified to determine the dosage of the diuretic compounds of this invention which will be most suitable and it Willvary with the form of administration, the particular compound chosen and the par ticular patient under treatment. It generally will be found that when the compounds are administered orally, larger 5 quantities of the active agent will be required. Useful dosages for human beings generally will be found to fall in the range between about 250 milligrams and 1.5 grams per day, although higher or lower dosages may be prescribed for both humans and mammals and the dosages may be administered in several different dosage units.

The following examples are given by way of illustration and are not to be construed as limitations upon the invention as many variations are possible without departing from the scope and the spirit thereof.

Example I 3,4-dichloro cinnamic acid may be prepared as follows, the quantities set forth forth hereinafter being on a weight basis.

A closable container is provided with a stopper carrying a calcium chloride guard tube. 44 parts of 3,4-dichlorobenzaldehyde, 57.5 parts of malonic acid, 125 parts of pyridine and 3 parts of piperidine are introduced into the container. After storage for seven days at a temperature of approximately 20 C. (68 F.), the reaction mixture is heated on a steam bath to a temperature between 90 C. (194 F.) and 100 C. (212 F.) for 24 hours while maintaining reflux conditions. The heated, refluxed mixture is then cooled to room temperature and stored for approximately four days. The liquid contents of the container are then poured, while maintaining strong agitation, into 100 parts of CP concentrated hydrochloric acid.

3,4-dich1oro cinnamic acid separates as a white precipitate which is recovered by filtration. The filter cake is purified by washing with 3% hydrochloric acid and then with water maintained at a temperature of approximately 10 C. (50 F.). Following washing, the filter cake is dissolved in warm 95% ethyl alcohol in a weight ratio of approximately 1:17. The alcohol solution is mixed with filter aids and filtered. The filtrate is then concentrated on a steam bath to approximately 50% of the original volume and then allowed to cool to approximately 10 C. (50 F.). The crystallizate is pure 3,4-dichloro cinnamic acid, M.P. 211 to 223 C. and is collected by filtration.

The potassium salt of 3,4-dich1oro cinnamic acid is prepared by titrating a suspension of the 3,4-dichlorocinnamic acid in methyl alcohol in a weight ratio of approximately 1:10 with aqueous solution of potassium hydroxide, using a glass electrode until a pH of 9.0 is indicated. The resulting solution is filtered and evaporated to dryness. The dried product consists of potassium salt of 3,4-dichl-oro cinnamic acid. It can be purified further by careful washing with dry methanol, filtration and drying.

Example 11 3,4-dichloro cinnamic may also be prepared as follows, the quantities being set forth hereinafter on a weight basis:

50 parts of 3,4-dichlorobenzaldehyde, 82 parts of freshly fused sodium acetate, 200 parts of acetic anhydride and 3 parts of pyridine are heated under reflux for about six hours in an oil bath maintained at a temperature of approximately 160 C. (320 F.). The reactant mixture is then cooled to approximately room temperature 20 C. (68 F.) and poured into 300 parts of water made up to 800 parts with crushed ice. 3,4-dichloro cinnamic acid precipitates immediately from the solution. The precipitate is filtered and washed with water maintained at a temperature of approximately C. (50 F.). The filter cake is dissolved in hot ethyl acetate in a weight ratio of approximately 1:15. The ethyl acetate solution is mixed with charcoal and filter aids and then filtered. The filtrate is concentrated on a steam bath to approximately 50% of the original volume and then allowed to cool to 10 C. (50 F.). The crystallizate is pure 3,4-dichloro cinnamic acid, M.P. 218 to 221.5 C. On thin layer chromatography the product is found to be substantially identical with that prepared in accordance with Example I.

4 Example III A mixture consisting of 35 parts of 3,4-dichlorobenzaldehyde, 19 parts of freshly fused sodium propionate and 32 parts of propionic anhydride is heated to an internal temperature in the range between C. and C. (266 F. and 275 F.) for approximately 30 hours while maintaining reflux conditions. The reactant mixture is then cooled to approximately 20 C. (68 F.) and poured into approximately 100 parts of water made up to 350 parts with crushed ice. A white product precipitate from solution and is recovered by filtration. The filter cake is washed with water maintained at a temperature of approximately 10 C. (50 F.).

The washed precipitate is suspended in methyl alcohol in a weight raito of approximately 1:10 and the suspension titrated with 10% aqueous solution of potassium hydroxide using a glass electrode until a pH of 7.4 is indicated. The resulting solution is filtered and evaporated to a thick syrupy concentrate. Upon storage at room temperature, a crystallizate is harvested which is the potassium salt of 3,4-dichloro-al-pha methyl cinnamic acid. Upon recrystallization from methyl alcohol, the reaction product is obtained as cream colored crystals having a melting point between 300 C. (572 F.) and 302 C. (575.6 F.).

Example IV 7 parts of 3,4-dichlorobenzaldehyde, 7 parts of paranitro-phenylacetic acid, 4 parts of pyridine and 4 parts of acetic anhydride are heated under reflux at approximately C. (302 F.) (bath temperature) for approximately 30 minutes. The reaction mixture is cooled to room temperature and diluted with 8 parts of CP concentrated hydrochloric acid and 20 parts of cold water. A fine precipitate which separates out of the aqueous acidic solution is recovered by extracting the solution with 300 parts of diethyl ether. The composite of ethereal solutions is washed twice with 100 parts of water maintained at a temperature of approximately 10 C. (50 F.) and the layers separated. The water washings are discarded.

The water washed ethereal solution is extracted four times in succession with 0.2% aqueous caustic soda solution using 250 parts of caustic solution for each extraction. The alkali extracted ethereal solution is then washed with water twice using 100 parts for each washing. The washings are added to the alkaline extracts of the ethereal solution. The combined aqueous alkaline solutions are acidified to pH 4.0 with acetic acid. The product, alpha-p-nitrophenyl-trans-3,4-dichloro cinnamic acid separates as a yellow precipitate which is recovered by filtration. Upon recrystallization of this product from ethyl acetate, a product is obtained having a melting point in the range between 220 C. (428 F.) and 224 C. (435.2 F.).

The filtrate, obtained following separation of the yellow precipitate, upon acidification with concentrated hydrochloric acid to a pH of 1.8 gives a recoverable quantity ,of alpha-p-nitro phenyl cis-3,4-dichloro cinnamic acid of melting point in the range between C. (365 F.) and 189 C. (372.2 F.).

Evaluation of the products of Examples I and III as a diuretic was made by the following test on a cat.

The potassium salt of 3,4-dichloro cinnamic acid was tested on a cat of 2.9 kilograms body weight. The cat was nembutal anesthetized and the bladder and the femoral veins cannulated. An infusion was made to produce a saline load of 20 ml. per kilogram of weight. 3,4-dichloro cinnamic acid (K salt) of Example I was dissolved in water and injected intravenously. Thereafter saline was added in amounts to continuously balance the urine output.

The result of testing the product of Example I is given in Table I and the analysis of the electrolyte excretion, ,aeq./ min. is given in Table II.

6 kilogram of weight. The product of Example IV was sus- TABLE I pended 1n 011 and administered mtramuscularly.

Period Urine Flow Urine Flow Urine Flow The result of testing the product of Example IV is -I e) Ratio given in Table IV.

5 TABLE IV Control 19. 6. 55 1.00

Group Urine Volume Urine Fow 10 mg./kg. 3,4-dichloro cinnamic acid (K salt) Per Hrs. (ml.) Ratio Hour 1 35. 0 12.1 1. 85 Control A 9. 5 1. 4 H0512 55.0 19.0 2. 90 ControlB 11.5 1.7 Standard (hydrochlorothiazide).-- 25. 0 3. 7 3,4-dicl1loro-alpha(-p-nitro 5 mg./kg, 3,4-dichloro cinnamic acid (K salt) phenyDcinnamic acid 18. 0 2. 7

5. 0 V Hours 106 0 36 6 6 Evaluation of the free acid, 3,4-d1chloro cmnamrc acid hl K It produced as an intermediate product in Example I as a slug [kg die om cmnamlc am Sa diuretic was made by the following test on a dog of 12.3 kilograms body weight. The do was tranquilized and a H 4 150.0 51.8 7.90 o

our retention catheter inserted 1nto the bladder. An infusion tube was then inserted into the foreleg vein. An infusion 5 .3,4,-dh1 dK 1t mg [kg m on) cmnamlc ac! Sa was made with a solution having 0.9% saline In 2.5% dextrose. The bladder emptied and liquid fed orally to H 5 135.0 46.6 7.13

our produce a saline load of 20 ml. per kilogram of we1ght. The dog was then induced to swallow a capsule containing TABLE II 300 mg. of 3,4-dichloro cinnamic acid.

The result of testing this free acid is given in Table V ElectmlYmExcremn (Fem/mm) and the analysis of the electrolyte excretion, neqJmin. is

given in Table VI. I K+ Cl- TABLE V g Period-- Urine Flow (ml.) Control 35.4 19.0 70.3 Control: 300 mg. 3,4-dichloro cinnamic acid Ahqmt Test 192-4 or 25 mg./kg. oral capsule 33.0

V Hour 1: 300 mg. 3,4-dichloro cinnamic acid Evaluation of the product of Example III as a diuretic 25 mg/kgoral 'f was made by the following test on cat. Hour 2: 300 mg. 3,4-d1chloro cinnamic acid The potassiumsalt of 3,4-dichloro-alph-a methyl cinor oral @Psule namic acid was tested on a cat of 2.59 kilograms body Hour 300 34dlchlom cmnamlc 361d weight. The cat'was nembutal anesthetized and the blador oral Capsule der and the femoralveins cannulated. An infusion was Hour 300 34'chl0mFmnam1c acld made to produce a saline load of 20 ml. per kilogram of or 25 mg/kg' 0m] capsule weight. The product of Example III was dissolved in Water TABLE VI and injected intravenously. Thereafter saline was added Electrolyte Excretion (/Leq./1I1in.) in amounts to continuously balance the urine output.

The result of testing the product of Example III is Na+ K+ 01- H60 given in Table III.

53.9 36.3 67.6 1 10 TABLE In 201.5 55.8 274.1 0.00 4 a at? as a: s-sa 'Pemd ggf fi g figgg 2029 3218 22515 00 control 5 1, 74 While a detailed description of the method of preparing Q p the diuretics of this invention, with some possible modifi- 5 mg./kg. 3,4-dichloro-alpha methyl cinnamic acid (K salt) cations, has been provided, it should be understood that g I numerous modifications may be aiIected without departing Hour 1 4.5 I i 1. 74 1.00. from the true spirit and scope of the concept of the invention. 5 mg./kg. 3,4-dichloro-alpha methyl cinnamic acid (K salt) I claim 1. The method of promoting diuresis in mammals Hour 2 5.0 1.93 1.11 which comprises administering to said mammals pharma- 5 mgJkg. 3,4-dichloro-alpha methyl cinnamic acid (K salt) Hour 3 8. 0 3. 08 1. 77

5 mgJkg. 3,4-dichloro-alpha methyl cinnamic acid (K salt) 5 mg. Ikg. 3,4-dichloro-alpha methyl cinnamic acid (K salt) Hour 5 The product of Example IV was tested with Holtzman male rats. The rats were tested in groups of four. An injection was made to produce a saline load of 20 ml. per

cologically active dosages of a compound selected from the wherein R represents a member selected from the group consisting of hydrogen, sodium and potassium; R represents a member selected from the group consisting of hydrogen, an alkyl having up to 3 carbon atoms, halogen, 75 phenyl, nitro substituted phenyl, and carboxyl; R represents a member selected from the group consisting of hydrogen and halogen; R represents a member selected from the group consisting of hydrogen and halogen, at least one of the substituents R and R always being a halogen.

2. The method according to claim 1 of promoting diuresis in mammals which comprises administering pharmacologically active dosages of a nuclear substituted cinnamic acid wherein both R and R are halogens.

3. The method of promoting diuresis in mammals which comprises administering to said mammals pharmacologically active dosages of 3,4-chloro cinnamic acid.

4. An article comprising a water soluble coating composition selected from the group consisting of ingestible synthetic gum and gelatin enclosing pharmacologically active dosage of between about 13 mgs. and 1.5 grams of a powdered compound of the formula wherein R represents a member selected from the group consisting of hydrogen, sodium and potassium; R represents a member selected from-the group consisting of hydrogen, an alkyl having up to 3 carbon atoms, halogen, phenyl, nitro substituted phenyl, and carboxyl; R represents a member selected from the group consisting of hy drogen and halogen; R represents a member selected from the group consitsing of hydrogen and halogen, at least one of the substituents R and R always being a halogen.

5. An article comprising a water soluble encapsulating material enclosing pharmacologically active dosage of between about 13 mgs. and 1.5 grams of a solution of a compound of the formula wherein R represents a member selected from the group consisting of hydrogen, sodium and potassium; R represents a member selected from the group consisting of hydrogen, an alkyl having up to 3 carbon atoms, halogen, phenyl, nitro substituted phenyl, and carboxyl; R represents a member selected from the group consisting of hydrogen and halogen; R represents a member selected from the group consisting of hydrogen and halogen, at least one of the substituents R and R always being a halogen.

6. An article comprising a water soluble encapsulating material enclosing pharmacologically active dosage of between about 13 mgs, and 1.5 grams of a vegetable oil solution of a compound of the formula l a CH=CCOOR1 wherein R represents a member selected from the group consisting of hydrogen, sodium and potassium; R represents a member selected from the group consisting of hydrogen, an alkyl having up to 3 carbon atoms, halogen, phenyl, nitro substituted phenyl, and carboxyl; R represents a member selected from the group consisting of hydrogen and halogen; R represents a member selected from the group consisting of hydrogen and halogen, at least one of the substituents R and R always being a halogen.

7. The method of promoting diuresis in mammals which comprises administering to said mammals pharmacologically active dosages of the potassium salt of 3,4-dichloro cinnamic acid.

8. The method of promoting diuresis in mammals which comprises administering to said mammals pharmacologically active dosages of the potassium salt of 3,4-dichloro-alpha methyl cinnamic acid.

9. The method of promoting diuresis in mammals which comprises administering to said mammals pharmacologically active dosages of alph-p-nitrophenyl-trans- 3,4-dichloro cinnamic acid.

References Cited UNITED STATES PATENTS 2,858,314 10/1958 Georgian. 2,969,372 1/1961 Braunetal.

OTHER REFERENCES Chemical Abstracts, vol. 58, entry 145980, 1963, citing Barre et al., Compt. Rend. Soc. Biol., 1956 1807-9 (1962).

LEWIS GO'ITS, Primary Examiner.

'ELBERT L. ROBERTS, Examiner.

R. L. HUFF, Assistant Examiner.

Edward M. Fletcher, Jr.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,345,263 October 3, 1967 Anangur V. Subbaratnam It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 3, line 13, strike out "forth", second occurrence; line 39, for "211" read 221 column 4, line 11, for

"precipitate" read precipitates Signed and sealed this 22nd day of October 1968.

(SEAL) Attest:

EDWARD J. BRENNER Attesting ()fficer Commissioner of Patents 

1. THE METHOD OF PROMOTING DIURESIS I MAMALS WHICH COMRISES ADMINISTERING TO SAID MAMMALS PHARMACOLOGICALLY ACTIBE DOSAGES OF A CMOPOUND SELECTED FROM THE GROUP HAVING THE FORMULA 